Various publications, including patents, published applications, technical articles and scholarly articles are cited throughout the specification. Each of these cited publications is incorporated by reference herein, in its entirety. Full citations for publications not cited fully within the specification are set forth at the end of the specification.
Severe sepsis is a multi-stage, multi-factorial and life threatening clinical syndrome that arises through the innate response to infection, and can appear as a complication in conditions like trauma, cancer and surgery. Despite important strides made in understanding its pathophysiology, the sepsis-related mortality and morbidity rates remain unacceptably high. Sepsis affects about 700,000 people and accounts for about 210,000 deaths per year in the United States alone.
In its most fulminate form, sepsis can produce cardiovascular collapse and death within hours. This variant of sepsis is almost always fatal in about 15% of patients receiving this diagnosis. More common is the development of multi-organ failure (MOF) secondary to hypoperfusion, histone release and intravascular thrombosis. In these variants of sepsis, MOF may be progressive and run a protracted clinical course, eventually proving fatal in 30-40% of patients. A variant of sepsis, affecting the remaining 30-40% of patients, involves a non-progressive MOF, in which the patient's condition can remain stable or improve during the first 48 hours of sepsis. Though they do not die, patients with this variant of sepsis can suffer long-term residual disabilities resulting from the sepsis-related tissue and organ damage.
The mechanisms responsible for the persistent and progressive or non-progressive organ failure are not fully understood. To examine this problem, non-human primate models of E. coli sepsis have been developed, which, depending on the bacterial dose, mimic the different pathophysiological syndromes observed in clinical practice (Taylor F B, Jr. 2001, Crit Care Med. 29: S78-89). Challenge with 1010 cfu/kg E. coli (LD100) results in an explosive inflammatory and coagulopathic response leading to irreversible shock and death. The administration of a lower dose, 109 cfu/kg E. coli (LD50) produces transient hypotension followed by MOF, which may progress and prove fatal in approximately 50% of the animals. Administration of still lower concentrations, 107-8 cfu/kg E. coli (LD10), produces a transient hypotension followed by MOF of less severity, which typically resolves in most patients, though residual long-term organ damage may result.
The pathophysiology of the LD50 model in particular demonstrates a two-stage or two-compartment response, each driven by distinct mechanisms. The first stage is an exacerbated intravascular host defense response to bacterial infection while the second stage is an uncontrolled extravascular host recovery response, which is believed to be driven at least in part by ischemia-reperfusion (IR) injury, leading to MOF. It is believed that both stages occur in the more severe (LD100) and the less severe (LD10) models of sepsis. However, in the LD100 model, the two stages overlap greatly, making it difficult to distinguish the two as having separate etiologies. Conversely, in the LD10 model, the biomarkers associated with both stages of sepsis are present, but are less evident due to the comparatively mild symptomology. Sepsis-induced release of histones into the blood has also been shown recently to be a major mediator of death in two animal models of sepsis (Xu, J et al., 2009, Nature Med. 15: 1318-1322).
Complement is critical for the innate immunity against pathogens, but uncontrolled complement activation has been associated with many immuno-inflammatory conditions (Markiewski M M et al., 2008, J Cell Mol Med. 12: 2245-2254). All three complement activation pathways, the classical (CP), the lectin (LP) and the alternative (AP), converge at C3, which is cleaved by CP-, LP- and AP-generated C3 convertases to C3a and C3b. The anaphylatoxin C3a activates platelets, induces their aggregation and recruits leukocytes. C3b participates in the formation of C5 convertase, which cleaves C5 to C5a and C5b, the latter becoming part of the terminal C5b-9 complex (TCC) (Markiewski M M & Lambris J D, 2007, Am J Pathol. 171: 715-727). Elevated levels of C5a could signal through its receptors C5aR and C5L2, contributing to immune paralysis, multi-organ dysfunction, apoptosis, deterioration of the coagulation/fibrinolytic system and contractile dysfunction of the cardiomyocytes (Ward P A, 2004, Nat Rev Immunol. 4: 133-142). Researchers have described a biphasic activation of the complement cascade in response to sublethal E. coli in baboons, with maximum peak of complement activation products occurring during the second stage (de Boer J P, et al., 1993, Infect Immun. 61: 4293-4301; Taylor F B, Jr., et al., 2006, Adv Exp Med Biol. 586: 203-216). It has been suggested that early increase of complement activation during sepsis may relate to bacteria opsonization (de Boer et al., 1993, supra; Bengtsson A, et al., 1993, Circ Shock. 39: 83-88), thus being beneficial in the host defense response. In contrast, complement activation during the second, extravascular stage of sublethal sepsis via either CRP or mannose-binding lectin (MBL) (Stahl G L, et al., 2003, Am J Pathol. 162: 449-455) can amplify the injury caused initially by oxidative stress and/or histone release. Such amplification acts as a positive feedback leading to a subsequent round of inflammatory activity localized in the tissues rather than in the vasculature, which in turn leads to aberrant responses unique to each tissue or organ, and finally to death in many cases.
Known methods for treating sepsis include antibacterials, antibodies, small molecules and peptides, activated protein C (APC), supportive therapy with oxygen, intravenous fluids, and medications that increase blood pressure. These treatments focus on the initial intravascular stage of sepsis and can rescue patients from sepsis that could otherwise be lethal. However, currently available treatments have not addressed the second stage of sepsis involving an uncontrolled extravascular host recovery response, which can lead to MOF and death. Likewise, complement inhibition has been proposed as a possible therapeutic avenue for treatment of sepsis, but again focusing only on the first stage of the syndrome involving intravascular complement activation in response to pathogen invasion (e.g., Laudes, I. J., et al., 2002, Am. J. Pathol. 160: 1867-1875; Bhole, D & G. L. Stahl, 2003, Crit Care Med. 31: S97-S104; U.S. Patent Publication No. 2007/0274989).
As can be seen from the foregoing discussion, there is a need in the art to identify and develop new methods for the treatment of sepsis, particularly focusing on the extravascular stage oxidative stress-induced events following ischemia reperfusion and histone release. This invention addressed those needs.